1. Field of the Invention
The novel semi-synthetic penicillins of the present invention are useful as antibacterial agents for the treatment of bacterial infections caused by gram-positive and gram-negative bacteria including especially Pseudomonas strains.
2. Description of the Prior Art
It is well-known that penicillin antibiotics generally inhibit the growth of various gram-positive and gram-negative bacteria and are effective in the treatment of infections caused by these organisms. It is also known that few penicillins exert any appreciable antimicrobial activity against Pseudomonas. For the last two decades, however, the incidence of Pseudomonas aeruginosa infection has progressively increased. Recently, some penicillin antibiotics have been synthesized which are reported to be useful as antipseudomonal antibiotics (e.g. carbenicillin, U.S. Pat. No. 3,142,673; sulbenicillin, U.S. Pat. No. 3,660,379; and ticarcillin, U.S. Pat. No. 3,282,926), but these penicillins exhibit only a relatively low potency against Pseudomonas aeruginosa necessitating the use of large amounts of them for effective treatment. Therefore, there remains a need for the synthesis of new penicillins which possess a high degree of anti-Pseudomonas activity.
Various N-acyl derivatives of ampicillin (or a derivative thereof in which the phenyl ring is replaced by substituted phenyl, thienyl or another aryl or heterocyclic radical) have been disclosed in the patent and scientific literature. Illustrative of those patents and patent publications disclosing such derivatives containing an .alpha.-heterocyclic-carboxamido group are:
A. U.S. Pat. No. 3,945,995 disclosing penicillins of the formula ##STR2## where R is an unsubstituted phenyl group or a substituted phenyl group having one or more hydroxyl groups or a cyclohexadienyl group and A represents a monocyclic or polycyclic nitrogen-containing heterocyclic aromatic ring. Triazine is listed in the disclosure as being included within the definition of substituent "A," but no penicillins having a triazine "A" group are illustrated or exemplified (see also U.S. Pat. No. 4,005,075).
b. U.S. Pat. No. 3,953,428 disclosing ampicillin derivatives of the formula ##STR3## where R is selected from various nitrogen, sulfur or oxygen-containing mono-, bi- or polycyclic heterocyclic rings. Triazine "R" substituents are not included within the scope of the disclosure.
c. Japanese Patent Publication No. 72189/73 (Farmdoc 79353U) disclosing penicillins of the formula ##STR4## where R.sup.1 and R.sup.2 are hydrogen, NH.sub.2, acylamino, alkylamino, OH, alkoxy, SH or alkylthio and X is N or CH. No penicillins are illustrated or exemplified having X.dbd.N, i.e. a 1,3,5-triazine ring.
d. U.S. Pat. No. 3,873,523 disclosing penicillins of the formula ##STR5## where R.sup.1 is one of several named alicyclic, aryl or heterocyclic radicals, R.sup.2 is hydrogen or, taken together with R.sup.1 represents the group ##STR6## and R.sup.3 is hydrogen or methyl (see also U.S. Pat. No. 3,948,903).
e. U.S. Pat. No. 3,951,955 disclosing penicillins of the formula ##STR7## where A is a substituted or unsubstituted condensed aromatic carbocyclic or heterocyclic ring, R is hydrogen or lower alkyl, X is oxygen or sulfur, Y is hydrogen, lower alkyl, lower alkanoyl or lower alkoxycarbonyl and Z is phenyl or thienyl. (See also U.S. Pat. No. 3,864,329).
f. U.S. Pat. No. 3,954,733 disclosing penicillins of the formula ##STR8## where A is a benzene ring or a 5 or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms, Z is a nitrogen atom or a methylene group, X is an oxygen or sulfur atom, Y is hydrogen, lower alkoxycarbonyl or lower alkanoyl, R.sub.1 is hydroxyl or protected hydroxyl and R.sub.2 and R.sub.3 are hydrogen or halogen.
g. U.S. Pat. No. 3,954,734 disclosing compounds of the formula ##STR9## where R.sub.3 is phenyl, p-hydroxyphenyl, 2-thienyl or cyclohexadienyl, R is hydrogen or methyl, R.sub.1 and R.sub.2 are hydrogen, C.sub.1 -C.sub.6 alkyl or R.sub.1 R.sub.2 N taken together is nitro or certain cyclic amines, X is hydrogen, chlorine or bromine and Y is hydrogen or bromine.
h. U.K. Pat. No. 1,440,216 disclosing compounds of the formula ##STR10## where R.sub.1 is hydrogen and R.sub.2 is optionally substituted phenyl, thienyl or furyl, n or m independently are 0 or 1 and B represents one of several named pyrimidyl radicals.
i. U.S. Pat. No. 3,320,240 disclosing compounds of the formula ##STR11## where R is an optionally substituted alkyl, aralkyl, aryl or heterocyclic group and X is a direct linkage or a divalent aliphatic, aromatic or heterocyclic radical which may be substituted.
j. U.S. Pat. No. 3,993,642 disclosing compounds of the formula ##STR12## where R.sub.1 is hydrogen, C.sub.1 -C.sub.5 alkyl, monoaralkyl, monoaryl, substituted monoaryl or thienyl, A is one of several named bivalent radicals including inter alia ##STR13## defined above for R.sub.1, E is oxygen or sulfur and B is optionally substituted phenyl or a thienyl, cyclohexenyl or cyclohexadienyl radical. (See also U.S. Pat. Nos. 3,923,789 and 3,974,288).
k. U.S. Pat. No. 3,939,150 disclosing penicillins of the formula ##STR14## where B is p-hydroxyphenyl or cyclohexadienyl, A is a 5- or 6- membered single or fused ring which may contain one or more nitrogen atom, an oxygen atom or a sulfur atom and R.sup.1, R.sup.2 and R.sup.3 each represent hydrogen, hydroxy, lower alkyl, nitro, halogen or an oxo group. No triazine "A" rings are disclosed in this patent.
l. French Patent Publication No. 2,191,556 (Farmdoc 23502U) disclosing penicillins of the formula ##STR15## where R' is lower alkyl and R.degree. is phenyl or chloro-substituted phenyl.
m. U.S. Pat. No. 3,433,784 disclosing penicillins of the formula ##STR16## where R is phenyl or thienyl, R' is optionally substituted heterocyclic and n is 0 or 1. No compounds are disclosed where n=0 and R' is a triazine radical.
n. West German Published Application No. 2,312,976 (Farmdoc 59216U) disclosing penicillins of the formula ##STR17## where ##STR18## is a heteroaromatic ring with 6 ring atoms of which 1 or 2 are nitrogen atoms, Y is hydrogen, (lower)-alkanoyl or (lower)alkoxy-carbonyl and R.sub.1 and R.sub.2 are each inter alia hydroxyl.
o. Japanese Patent Publication No. 52790/73 (Farmdoc 64733U) disclosing the penicillin of the formula ##STR19## and
p. West German Published Application No. 2,457,464 disclosing penicillins of the formula ##STR20## where A is optionally substituted phenyl, optionally substituted monocyclic aromatic heterocyclic or dihydrophenyl and X is --SO.sub.2 --, --CO--, --P(R)-- or --P(O)(R) in which R is optionally substituted lower-molecular alkyl, alkenyl, alkoxy, aralkyl, aralkoxy, aryl or aryloxy.